The epidermal growth factor receptor (Egfr) is a transmembrane receptor tryrosine kinase that is required in numerous tissues during development and is associated with many forms of cancer. From mouse knockout studies, the Egfr is known to be required for the maturation and/or maintenance of the mature intestinal tract. Furthermore, genetic evidence suggests that the Egfr is required during colorectal tumorigenesis. This is despite that fact that the gene encoding Egfr is not known to be mutated during colorectal cancer development. Although cancer of the colon and rectum is the third most frequently diagnosed cancer in the United States and accounts for the second largest number of cancer deaths, the role of only a few genes has been studied in detail; these genes are typically mutated during colorectal tumorigenesis or are associated with familial forms of the disease. Little is know about genes that appear to be required for the progression of tumorigenesis but do not become mutated themselves like Egfr. The objectives of the proposed research are therefore (1) to investigate the global importance of Egfr during development of colorectal cancer, (2) to determine the temporal requirement for Egfr during colorectal cancer development, (3) to define the mode of action of Egfr during tumorigenesis, and (4) to investigate the function of Egfr in non-epithelial compartments of the gastrointestinal tract.